DE2813287A1 - PROCESS FOR THE MANUFACTURING OF 2-BENZOYL-3,3-DIMETHYL-7-OXO-ALPHA- (4-BENZYLOXYPHENYL) -4-THIA-2,6-DIAZABICYCLO-SQUARE CLAMP ON 3.2.0 SQUARE CLAMP FOR HEPTANE-6-VACUINE ACID BENZYLE - Google Patents

Description

P 28 13 287.8 X-4883

ELI LILLY AND COMPANY, INDIANAPOLIS, INDIANA, V. ST. A.

Process for the preparation of 2-benzoyl-3,3-dimethyl-7-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicycl · o- / 3 ~. ^ .oTheptane-e-acetic acid benzyl ester

The invention relates to a new process for preparing the compound of the formula

_o ^HsC v / *

wherein the designated carbon atom has the D configuration, the compound in the L configuration or as a mixture of D with L configuration being dissolved in aqueous pyridine , from which the compound with the D configuration crystallizes out selectively.

809842/0688

In the method according to the invention, the asymmetry center, which is attached to the nitrogen of the azetidinone ring of the compound is bound, epimerized with selective formation of the D configuration. The bicyelic compound of the above For the sake of simplicity, the formula is hereinafter referred to as thiazolidinazetidinone designated. From a formal point of view, its full name is 2-benzoyl-3,3-dimethyl-7-oxo-alpha- (4-benzyloxyphenyl) ~ 4-thia-2,6-diazabicyclo / 3.2.0 / heptane-6-acetic acid benzyl ester. In the D configuration, the compound is suitable as an intermediate for the production of the antibiotic nocardicin. This epimerization of the starting material takes place, which leads to a mixture of D- and L-thiazolidinazetidinone. The two isomers can be separated from one another by fractional crystallization, but that according to the invention Process enables the conversion of the L-isomer into the D-isomers, as a result of which losses in the yield of the end product are considerably reduced.

The invention is a method for producing the Compound of formula

0 " ³ V /"

COOCHs

in the D configuration, this compound being in the L configuration or as a mixture of L- and D-configuration in one

809842/0668

Temperature of 20 to 30 ⁰ C in a concentration of 50 to 100 mg / ml in pyridine, the solution is diluted with water in an amount of 10 to 50 percent by volume and the compound is separated off in the D configuration.

Under the conditions according to the invention of temperature, concentration and the volume ratio of water: pyridine D-thiazolidinazetidinone is the least soluble of the two isomers and precipitates selectively from the epimerization mixture. If the concentration in , the aqueous pyridine coincides somewhat with the D-form L-thiazolidinazetidinone. If the water content is above 50 percent by volume, the D- and L-forms can also be used fail together. Under the conditions of the method according to the invention, however, experiences about in the epimerization mixture L-thiazolidine acetidinone present a conversion to the D configuration in the presence of the basic pyridine and due to the lower solubility of the D-isomer in the aqueous pyridine, it precipitates selectively, whereas the more strongly soluble LH configuration remains in solution and further epimerization learns.

The process according to the invention is preferably carried out in pyridine with a water content of 15 percent by volume and a thiazolidinazetidinone concentration from 50 to 75 mg / ml.

The epimerization process of the present invention is illustrated by the following reaction scheme in which only the essentials Part of the structural formulas of the Thiazolidinazetidinone is given.

L .coocM

β y> QC »z0 \

809842/0668

The thiazolidinazetidinone is formed by basic cyclization of a salpha-chlorothiazolidinamide in the D configuration then epimerization occurs. The ratio of D- to L-thiazolidinazetidinone that is obtained here, is due to the determination by high pressure liquid chromatography at around 70:30.

Since when carrying out the epimerization process according to the invention the less soluble D-isomer precipitates out of the mixture, the ratio of D- to L-isomer is constant again to about 70:30, creating more D-isomer, which in turn precipitates.

The preparation of the Thiazolidinazetidinons is by the following Reaction scheme illustrated. L-cysteine is heated with acetone and the 2, 2-dimethylthiazolidine-4-carboxylic acid (1) becomes 2,2-dimethyl-3-benzoyl-thiazolidine-4-carboxylic acid with benzoyl chloride in the presence of a hydrogen halide acceptor (2) acylated. The latter compound is then formed into that with the benzyl ester of 4-benzyloxyphenylglycine Amide (3) transferred. The amide is expediently formed such that first the Thxazolidxncarbonsäure by condensation with the Hydroxybenztriazol in the presence of a Condensing agent, such as dicyclohexylcarbodiimide, is converted into an active ester, which is then used to acylate the alpha-amino group of phenylglycine is used to form the amide (3).

8 0 9 8 A 2/0 6 6 8 · "'~ ^U

-JiT-

NHa I.

L CH-CHz-SH I COOH

+ Acetone

(D

—C-ci

COOH

, CHs

(2) as an active ester +. H ₂ N-CH-

(D

H ₃ Q CH ₃ \ / ·

Π-

. ι

C = O

NH

Λ β.

COOCH ζ-Κ

■ (3)

4 2/0688

The thiazolidinamide (3) is converted into the cyclic thiazolidinazetidinone as shown in the following reaction scheme of formula I converted.

⁺ Benzoyl peroxide

HCJ \

CHs. pt
O \ /

COOCHsji

0 I! • O-C0

CH- <

T = '

COOCH ₂ JZf

V-O-CHe-J *

(5)

Na (H) \ JZi-C-!

CH ₃ . / CHi O \ /

(f

■ —io ^H

A — C— K / «- C-CHs-

9 842/0668

As shown, the thiazolidine axnide (3) is first carried out by Reaction with benzoyl peroxide converted into the 5alpha-benzoate derivative (4). The reaction is carried out by heating the amide carried out in an inert solvent with benzoyl peroxide. Suitable solvents include the hydrocarbon solvents, like benzene and toluene and the chlorinated hydrocarbon solvents, such as methylene chloride and chloroform. The benzoyl peroxide is in excess, preferably in about 2 to 4 molar excess applied.

The Sälpha-Benzöat (4), which can be purified by chromatography on silica gel and separated from unreacted starting material, is then treated with hydrogen chloride in an inert solvent at a temperature of about -20 to 5 ⁰ C to the corresponding Salpha-Chlorthiazolidinamid of formula ( 3) implemented. The reaction is conveniently carried out in a chlorinated hydrocarbon solvent such as methylene chloride or. Chloroform carried out, and the course of the reaction can be followed by thin layer chromatography.

On treatment with a strong base, such as sodium hydride or 1 _/ S-'Dia? Abicyclo / 5.4.0 / undec-5-en (DBU) under anhydrous conditions, the 5alpha-chlorine compound (5) undergoes ring closure to the bicyclic thiazolidinazetidinone.

The ring closure is carried out at a temperature of 0 to 30 ⁰ C in an inert solvent. Suitable solvents include those mentioned above in connection with the preceding reactions, for example the halogenated hydrocarbon solvents such as chloroform, DMF and methylene chloride, as well as trichloroethanes. The cyclization product is best purified by chromatography on silica gel. The system of benzene and benzene with increasing proportions of ethyl acetate up to a volume ratio of 7s3 is suitable for the gradual elution.

809842 / 0S6

The base-catalyzed cyclization of 5alpha-chlorothiazolidine carboxamide leads to epimerization of the asymmetry center in the phenylglycine part of the amide. When using D-phenylglycine as the starting material for the Production of the bicyclic Thiazolidinazetidinons leads, thus the base-catalyzed cyclization with epimerization to a mixture of D- and L-thiazolidinazetidinone. The two isomers can be separated from one another by fractional crystallization, but this is possible with associated large yield losses, which are avoided by the method according to the invention, because it is possible with it is to convert the L-isomer into the desired D-isomer .

As mentioned above, the D-Thiazolidinazetidinon obtained by the process of this invention is a valuable product for the synthesis of the antibiotic Nocardicin.- For this, the D-Thiazolidinazetidinon in an inert solvent at a temperature of 0 to 5 ⁰ C with an oxidizing agent such as m -Chlorperbenzoic acid to the corresponding sulfoxide of the formula

CH ₃ . .Ci
O \ _ /

implemented. The SuIfoxid is then made up in a mixture Dimethylacetamide and benzene refluxed with methanesulfonic acid, whereby the thioketone-substituted Azetidinone of the formula

809842/0668

OH I »

Il 1 ^ -CHa-C-CHa

/ Zf-C-N-t-t

Cf

'cOOCHsjZf

is obtained.

The substituted Atezidinon is reacted at a temperature of about 0 ⁰ C and sulfuryl chloride, and the resulting reaction mixture is isolated and dissolved in toluene with a 3-molar excess of tri (η-butyl) -zinnhydrid in the presence of a 3-molar excess of azobisisobutyronitrile to the 3-benzoylaminoazetidinone of the formula

0 H Il I

V- <

implemented.

The 3-benzoylaminoazetidinone ester of those given above Formula is deacylated to the corresponding 3-aminoazetidinone ester as follows. The 3-benzoylamino compound is dissolved in dry methylene chloride and treated with excess phosphorus pentachloride. After adding

80 9842/0668

Pyridine in an _{amount equimolar to the PCl 5} , the mixture is stirred for about 30 minutes at room temperature. ^{It is then cooled to about 5 °} C. in an ice bath and excess dry methyl alcohol is added. The reaction mixture is stirred in the cold for about 10 minutes, after which it is diluted with water and allowed to warm to room temperature. The 3-aminoazetidinone ester is extracted from the reaction mixture and conveniently isolated in the form of an acid addition salt, for example as p-toluenesulfonate or hydrochloride. The 3β-aminoazetidinone free ester of the following formula is obtained by treating the salt with a weak base.

HaN- ·? -— t _e __.
1 — N-CH-ef ' \ *

<f, W

COO-CH2-0

The 3-aminoazetidin-2-one of the formula given above is an esterified and hydroxy-protected nocardicin scaffold. The backbone is made with an amino-protected ester 4- (D-S-Amino-S-carboxypropoxy) -phenylglyoxylic acid-O-acyloxime acylated to the nocardicin precursor in which amino, hydroxy, carboxyl and oximino groups are protected. The acylation is illustrated by the following reaction scheme.

809842/0668

ο. . ο ■ ■

R'-O-C-CH-CHa-CHs-O- · '^ e-C-C-OH + nocardicine skeleton

I \ / Il

N-H N-Q acyl

1
R "

O OH

f NCC — N * —f _n __ _%

R'-O-O-CH-CHa-CHe-O-tf N-C-C-N

1 ( ₁ CH-C VoCH 0

NH N-QAcyl tf , \ - _% ^/ *

^1st COO-CHs ^ R ".

In the formulas given above, R ¹ denotes a carboxylic acid protecting group which can be easily removed under acidic conditions, for example a diphenylmethyl, benzyl, 4-methoxybenzyl, 2,4,6-trimethylbenzyl or phthaliraidomethyl group and R2 an amino protecting group, for example the t-butyloxycarbonyl group and acyl stands for an acetyl, chloroacetyl or dichloroacetyl group.

The acylation can be carried out by linking the glyoxylic acid-O-acyloxime with the free 3ß-amino group of the framework compound in the presence of a condensing agent such as carbodiimide or by forming a mixed anhydride of glyoxylic acid-O-acyloxime and reaction of this anhydride with the 3β-amino skeleton carried out in the presence of triethylamine will.

809842/0668

The preferred acylation method is the former, the acylation of the amine skeleton being carried out with the aid of a condensing agent. For example, the 3β-amino skeleton ester is reacted in an inert solvent such as methylene chloride or tetrahydrofuran with the phenylglyoxylic acid-O-acyloxime with a split amino and split carboxyl group in the presence of an equimolar amount or a small excess of a carbodiimide , such as dicyclohexylcarbodiimide. To achieve the best results, the reaction mixture is kept practically anhydrous. The reaction is carried out with stirring at about room temperature. After the reaction, the insoluble dicyclohexylurea is filtered off and the acylation product is obtained from the filtrate.

The esterified phenylglyoxylic acid with a protected amino group is prepared according to the procedure described below. A protected amino group of D-methionine of the formula

0 H
MOCC-CH ₂ -CH ₂ -S-CH ₃ ,

NH

I I

in which M, for example, is a dicyclohexylammonium group and R ″ has the meaning given above, is converted into the trimethylsilyl ester converted and alkylated on sulfur with an alkyl iodide, e.g. methyl iodide, or with benzyl iodide. The alkyl sulfonium iodide the formula

OH ₊ j (CH-.), .Si-OCC-CH ₀ -CH ₀ -S-CH-

NH CH-.

809842/0668

is made in an inert solvent with potassium t-butoxide too the cyclic D-homoserine lactone with a protected amino group the formula

■ - ■■ '- H

D R "-N-e,

Il
. 0

implemented. The lactone becomes the with an alkali hydroxide Alkali salt of D-homoserine with a protected amino group of the formula

H H

R ¹ '-NC-CH "-CH" -OH COOM ¹

wherein M ^{1 is} sodium or potassium, hydrolyzed, and the last-mentioned salt is esterified, for example with diphenyl methyl bromide. The esterified D-homoserine is then with a 4-hydroxyphenylglyoxylic acid ester, for example the p-nitrobenzyl ester, in the presence of trialkyl or triarylphosphine, preferably triphenylphosphine, and diethylazodicarboxylate linked, whereby the diester with a protected amino group of the formula

OH 0

Il I · - · _Ν Il y * ~~ '\

R'-OCC-CHs-CHs-O- ^ SC-COO-CHz-eC S-NOs ! · = · ^/ \ = S

NH
I.
R "

809842/0668

is obtained. The p-nitrobenzyl ester group is selectively removed by reduction, the other ester group R ¹ , which is an acid-labile ester group, being essentially retained. For example, the p-nitrobenzyl ester group is removed by reduction with sodium sulfide, the ester group R ¹ , which is an acid-sensitive group, e.g. B. the diphenylmethyl group is not attacked. The product

the selective ester cleavage, which corresponds to phenyl glyoxylic acid the formula

OH 0

Il I. · - * x Il

R'-O-C-C-CHs-CHs-O- · ^) # - C-COOH. I e = o

NH

R "

The phenylglyoxylic acid of the formula given above is then converted to the oxime with hydroxylxmine hydrochloride in an aqueous organic solvent in the presence of a weak base such as sodium carbonate or sodium bicarbonate. The oxime is obtained from the reaction mixture by conventional procedures and converted into the O-acyloxime, e.g. B. converted the acetyl, chloroacetyl or dichloroacetal derivative. After the acylation of the nocardicin skeleton ester carried out as above, the nocardicin precursor "(nocardicin with protected carboxyl, hydroxy, amino and oxime functions) is reacted with trifluoric acid, whereby the acid-labile protective groups, namely the O-acyl group of the oxime, the R ¹ ester group, For example, the .Diphenylmethylestergruppe and the amino protecting group, such as the t-butyloxycarbonylamino protecting group are removed The partially deblocked product is then reacted with aluminum chloride, whereby the benzyl ester group and the benzyl group of the 4-benzyloxy group are removed;

809842/0668

The invention is further illustrated by the following examples.

example 1

A solution of 3.3 g of D _/ L-2-Benzoyl-3,3-dimethyl-7-oxo-alpha- / 4- (benzyloxy) -phenyl / -4-thia-2,6-diazabicyclo / 3.2. 0 / heptane-6-acetic acid benzyiester (mixture of 50 parts by weight of D and 50 parts by weight of L compound) in 35 ml of pyridine is diluted with 5.25 ml of water and left to stand for 18 hours at room temperature. The crystalline precipitate is filtered off and washed with cold diethyl ether, whereby 1.97 g of the D-isomer are obtained. A second crop of D-isomer of 0.47 g is obtained from the filtrate and a third crop of 0.43 g is obtained from the filtrate of the second crop.

ΐ "■" "," "Example 2

To a solution of 4.1 g of L-2-benzoyl-3,3-dimethyl-7-ox; o-alpha- / 4- (benzyloxy) -phenyl / -4-thia-2,6-diazabicyclo / 3.2. 0 / heptane-6-acetic acid benzyl ester 7.5 ml of water are added to 50 ml of pyridine. The solution is about 8 hours at room temperature stirred and the crystalline precipitate from the D-isomer is filtered off. The product is dried, yielding 2.45 g Substance and a further 0.95 g of precipitated substance from the filtrate are obtained.

8 09842/0668

Claims (4)

PATENT CLAIMS 1. Process for the preparation of 2-benzoyl-3,3-dimethy1-7-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo_ / 3 .2 .0 / -heptane-6-acetic acid benzyl ester the formula ■ o ^H3 \ / ^h · - ·. Il / <Vo- / C00CH2— · 'y> (D-configuration), characterized in that the L-configuration or a mixture of the L- and D-configuration of this compound is dissolved at a temperature between 20 and 30 ⁰ C in pyridine up to a concentration of 50 to 100 mg / ml , the solution is diluted with water in an amount corresponding to 10 to 50 percent by volume, and the compound in the D configuration is separated. 2. The method according to claim 1, characterized in that that the pyridine solution is diluted with water in an amount corresponding to 15 percent by volume will. 809842/0868 3. The method "according to claim 1 or 2, characterized in that the L-configuration the compound is used as a starting material. 4. The method according to claim 1 or 2, characterized in that a mixture of D and L-configuration of the compound is used as the starting material. 809842/0668